NRF2 Activation in Autophagy Defects Suppresses a Pharmacological Transactivation of the Nuclear Receptor FXR

Abstract

NF-E2-related factor 2 (NRF2), an antioxidant transcription factor, is activated in autophagy-deficient mice due to the accumulations of p62/SQSTM1 and its subsequent interaction with Kelch-like-ECH-associated protein 1 (KEAP1), an adaptor component for Cullin3-based E3 ubiquitin ligase complex. Farnesoid x receptor (FXR/NR1H4) is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. FXR plays an essential role in bile acid synthesis and enterohepatic circulation, affecting glucose and lipid metabolism. Obeticholic acid as a potent FXR agonist has been approved to treat primary biliary cholangitis and clinical trials for its use in the treatment of other liver diseases are underway. Here we show that NRF2 activation in autophagy defects impedes a transactivation of FXR. Liver-specific Atg7 knockout mice or a treatment of autophagy inhibitor showed decreased inductions of FXR target genes upon its synthetic agonists. Moreover, enforced NRF2 activations with small molecules potently decreased the pharmacological activation of FXR in cultured cells. Finally, we demonstrate that NRF2 activation by the treatment with the food antioxidant butylated hydroxyanisole is necessary and sufficient to inhibit the pharmacological activation of FXR in vivo. These results reveal a novel function of the basal autophagy-NRF2 axis for the regulation of FXR transactivation, and shed light on a potential therapeutic strategy in metabolic disease.